While multiple etiologies are likely to account for Parkinson's disease (PD), the core pathogenic feature is degeneration of dopaminergic neurons, particularly those in the substantia nigra pars compacta (SNpc), with shared common final pathways involving oxidative damage, mitochondrial dysfunction, or both. Therefore, one may hypothesize that dopaminergic neurons in the SNpc are selectively vulnerable to oxidative stresses and/or mitochondrial disruption and understanding the mechanism of this selectivity may reveal the pathogenesis. However, our data show that ventral mesencephalic dopaminergic neurons in culture have an enhanced antioxidant capacity, as they are better able to resist oxidative stresses such as glutathione depletion and peroxide treatment than nondopaminergic neurons. In addition, their enhanced antioxidant capacity is reflected in lower reactive oxygen species (ROS) and higher reduced glutathione levels than nondopaminergic neurons. We hypothesize that an enhanced antioxidant capacity is essential for the survival of dopaminergic neurons that may be subjected to increased oxidative stress exerted by dopamine and its metabolites. We postulate that disruption of this innate antioxidant capacity makes them vulnerable to additional environmental insults and thereby leads to selective degeneration. We noted that the enhanced antioxidant capacity in ventral mesencephalic dopaminergic neurons is due to tetrahydrobiopterin (BH4), which is the cofactor for tyrosine hydroxylase, the enzyme producing dopamine, but also lowers superoxide levels, partly be direct scavenging effect and modulates mitochondrial function. First, We will study the effect of BH4 on mitochondrial bioenergetics and function including initiation of death pathways. Second, we will examine the role of BH4 on NO and superoxide generation and in modulating other endogenous antioxidant systems. Third, the neuroprotective function of BH4 against PD models such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone toxicity, and glutathione depletion will be tested in vivo and in organotypic slice cultures, using hph-1 mice that are deficient in BH4, production.